One aim of this project is to use transcranial magnetic stimulation (TMS) of the brain to study physiological changes in different behavioral states and disorders. Since finding evidence of increased cortical excitability in obsessive-compulsive disorder (OCD), we have looked for an association between neurophysiological data and behavioral measures in the general population, using a dimensional approach. We found a highly significant positive association between the tendency to experience negative emotion ("Neuroticism" in the 5-factor personality model) and cortical excitability measured with paired-pulse TMS which reflects cortical GABA-glutamate balance. We hypothesize that a condition of heightened excitability, as exists in high "Neuroticism" individuals, should predispose to the development of long-term potentiation (LTP) of cortical synapses. We are looking for evidence of this with behavioral and electrophysiological tests before and after motor learning, again using a dimensional approach where possible. We further hypothesize that aberrant formation of associative LTP may underlie the development of OCD, focal dystonia, and other disorders and are initiating parallel studies to test these hypotheses. We have also initiated a study of the the possible contribution of genetic polymorphisms to the behavioral and neurophysiological dimensions mentioned above. For instance, we hypothesize that polymorphisms, such as that in the 5-HT transporter promoter region or the 5-HT1A receptor may contribute both to personality and to cortical excitability through their influence on GABAergic activity in the cortex. Other genes under study affect the 5-HT, dopamine, and GABA neurotransmitter systems. TMS measures of cortical excitability may provide intermediate phenotypes for genes affecting neural function and behavior